Metabolic syndrome is a common disease characterized by glucose disorders and dyslipidemia, accompanied by elevated LDL-c levels and reduced HDL-c levels. Metabolic syndrome mainly includes obesity, diabetes, hyperlipidemia and atherosclerosis, wherein the diabetic patients are also often complicated with hyperlipidemia, cardiovascular disease, diabetic nephropathy, diabetic neuropathy and other diseases.
World Health Organization has reported that more than 220 million people are suffering from diabetes worldwide. China has become the country with world's highest number of diabetic patients. According to the data of research report published on “The New England Journal of Medicine” on Mar. 25, 2010, there have been more than 92 million diabetic patients in China. Incidence and growth rate of diabetes are significantly increasing now. It is estimated that China has 150 million pre-diabetics currently. Continued expansion of the diabetic population has brought enormous economic and medical burden to the society. World Health Organization has pointed out that heart disease, stroke and diabetes will bring at least $550 billion losses in economic to China in next 10 years if no effective measures are taken to contain the development of these diseases.
It has been shown that pharmacological activations of peroxisome proliferator-activated receptors (PPARs) are effective therapeutic approaches to correct some aspects of metabolic syndrome mainly hyperlipidemia and type II diabetes mellitus. PPARs belong to the superfamily of nuclear hormone receptors that function as ligand-inducible transcription factors modulating the expression of target genes, which include three subtypes PPAR α, PPAR β/δ and PPAR γ (Feige J N, Gelman L, Michalik L, Desvergne B, & Wahli W (2006) From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Progress in lipid research 45(2):120-159.). PPARs can not only regulate glucose homeostasis, lipid metabolism, and inflammation, but also accommodate obesity, cell differentiation and cancer (Desvergne B & Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine reviews 20(5): 649-688; Moraes L A, Piqueras L, & Bishop-Bailey D (2006) Peroxisome proliferator-activated receptors and inflammation. Pharmacology & therapeutics 110(3): 371-385.).
Specific lipid-lowering drug fibrates have been used in the treatment of dyslipidemia via a PPAR α-dependent activating mechanism (Issemann I, Prince R A, Tugwood J D, & Green S (1993) The peroxisome proliferator-activated receptor: retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. Journal of molecular endocrinology 11(1): 37-47.). PPAR γ agonist thiazolidinediones (TZDs), such as rosiglitazone (ROS) and pioglitazone on the market now, are very effective in improving glycemic management (Lehmann J M, et al. (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). The Journal of biological chemistry 270(22): 12953-12956.). Dual PPAR α/γ agonists may provide enhanced therapeutic value for the treatment for complicated metabolic syndrome. A lot of pharmaceutical and clinical trials have investigated the collective effects of dual PPAR α/γ agonists on sustained glucose, lipid and inflammation control (Staels B & Fruchart J C (2005) Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 54(8): 2460-2470.). Despite their excellent potencies, dual agonists, including ragaglitazar, MK-0767, muraglitazar and aleglitazar, have been withdrawn from clinical studies because of obvious adverse effects (Nissen S E, Wolski K, & Topol E J (2005) Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA: the journal of the American Medical Association 294(20): 2581-2586.). Thus, development of novel, effective and safer dual PPAR α/γ agonist is urgently needed.